Association between Obesity and Circulating Brain-Derived Neurotrophic Factor (BDNF) Levels: Systematic Review of Literature and Meta-Analysis.
Reduction in brain-derived neurotrophic factor (BDNF) expression in the brain as well as mutations in BDNF gene and/or of its receptor are associated to obesity in both human and animal models. However, the association between circulating levels of BDNF and obesity is still not defined. To answer this question, we performed a meta-analysis carrying out a systematic search in electronic databases. Ten studies (307 obese patients and 236 controls) were included in the analysis. Our data show that obese patients have levels of BDNF similar to those of controls (SMD: 0.01, 95% CI: -0.28, 0.30, p = 0.94). The lack of difference was further confirmed both in studies in which BDNF levels were assessed in serum (MD: -0.93 ng/mL, 95% CI: -3.34, 1.48, p = 0.45) and in plasma (MD: 0.15 ng/mL, 95% CI: -0.09, 0.39, p = 0.23). Data evaluation has shown that some bias might affect BDNF measurements (e.g., subject recruitment, procedures of sampling, handling, and storage), leading to a difficult interpretation of the results. Standardization of the procedures is still needed to reach strong, affordable, and reliable conclusions.


Cell-line and tissue-specific signatures of androgen receptor-coregulator transcription.
Normal genital skin fibroblasts (GSF) and the human prostate carcinoma cell line LNCaP have been used widely as cell culture models of genital origin to study androgen receptor (AR) signaling. We demonstrate that LNCaP shows a reproducible response to androgens as assessed using cDNA-microarrays representing approximately 32,000 unique human genes, whereas several independent GSF strains are virtually unresponsive. We show that LNCaP cells express markedly higher AR protein levels likely contributing to the observed differences of androgen responsiveness. However, previous data suggested that AR-expression levels alone do not determine androgen responsiveness of human GSF compared to LNCaP. We hypothesized that cell-specific differences in expression levels of AR coregulators might contribute to differences in androgen responsiveness and might be found by comparing LNCaP and GSFs. Using the Canadian McGill-database of AR coregulators ( http://www.mcgill.ca/androgendb ), we identified 61 AR-coregulator genes represented by 282 transcripts on our microarray platform that was used to measure transcript profiles of LNCaP and GSF cells. Baseline expression levels of 48 AR-coregulator transcripts representing 33 distinct genes showed significant differences between GSF and LNCaP, four of which we confirmed by reverse transcriptase polymerase chain reaction. Compared to LNCaP, GSFs displayed significant upregulation of AR coregulators that can function as repressors of AR-transactivation, such as caveolin 1. Analysis of a recently published comprehensive dataset of 115 microarrays representing 35 different human tissues revealed tissue-specific signatures of AR coregulators that segregated with ontogenetically related groups of tissues (e.g., lymphatic system and genital tissues, brain). Our data demonstrate the existence of cell-line and tissue-specific expression patterns of molecules with documented AR coregulatory functions. Therefore, differential expression patterns of AR coregulators could modify tissue-specificity and diversity of androgen actions in development, physiology, and disease.


Biology and pathogenesis of chikungunya virus.
Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus responsible for a recent, unexpectedly severe epidemic in countries of the Indian Ocean region. Although many alphaviruses have been well studied, little was known about the biology and pathogenesis of CHIKV at the time of the 2005 outbreak. Over the past 5 years there has been a multidisciplinary effort aimed at deciphering the clinical, physiopathological, immunological and virological features of CHIKV infection. This Review highlights some of the most recent advances in our understanding of the biology of CHIKV and its interactions with the host.


Adaptive Resilient Event-Triggered Control Design of Autonomous Vehicles With an Iterative Single Critic Learning Framework.
This article investigates the adaptive resilient event-triggered control for rear-wheel-drive autonomous (RWDA) vehicles based on an iterative single critic learning framework, which can effectively balance the frequency/changes in adjusting the vehicle's control during the running process. According to the kinematic equation of RWDA vehicles and the desired trajectory, the tracking error system during the autonomous driving process is first built, where the denial-of-service (DoS) attacking signals are injected into the networked communication and transmission. Combining the event-triggered sampling mechanism and iterative single critic learning framework, a new event-triggered condition is developed for the adaptive resilient control algorithm, and the novel utility function design is considered for driving the autonomous vehicle, where the control input can be guaranteed into an applicable saturated bound. Finally, we apply the new adaptive resilient control scheme to a case of driving the RWDA vehicles, and the simulation results illustrate the effectiveness and practicality successfully.


Curcumin-based pyrazoline analogues as selective inhibitors of human monoamine oxidase A.
A series of 2-methoxy-4-(5-phenyl-4,5-dihydro-1H-pyrazol-3-yl)phenol (pyrazoline) derivatives (2-6) have been synthesized and tested for human monoamine oxidase (hMAO) inhibitory activity. The most active derivative (2) behaved as a competitive hMAO-A inhibitor, with an inhibition constant value of 0.08 μM and a strong hMAO-A selectivity (Ki(hMAO-B)/Ki(hMAO-A) > 1751). In addition, 2 exhibited little to no cytotoxic effects up to a 25 μM concentration and provided the best blood-brain barrier permeability among the derivatives synthesized. Molecular dynamics simulations revealed that a chlorine substituent at the para-position of the phenyl ring in 2 enabled a π-π stacking interaction with Tyr407 and Tyr444 that resulted in the formation of an "aromatic sandwich" structure. Consequently, this tight-binding aromatic cage culminated in a dramatically reduced active site volume that is believed to be the origin of the observed selectivity between the hMAO-A and hMAO-B isozymes. Removal of the chlorine from 2 disrupted the favorable intermolecular interactions and resulted in a selectivity change towards hMAO-B.


Femtosecond direct space-to-time pulse shaping in an integrated-optic configuration.
We demonstrate femtosecond operation of an integrated-optic direct space-to-time pulse shaper for which there is a direct mapping (no Fourier transform) between the spatial position of the masking function and the temporal position in the output waveform. The apparatus is used to generate trains of more than 30 pulses as an ultrafast optical data packet over approximately an 80-ps temporal window.


Comparison of in vivo airway responsiveness and in vitro smooth muscle sensitivity to methacholine in man.
Airway responsiveness to methacholine varies between normal people and is increased in patients with asthma. The importance of airway smooth muscle sensitivity in determining in vivo responsiveness is unknown. We have examined this question by comparing in vivo airway responsiveness with in vitro airway smooth muscle sensitivity to methacholine in 10 patients undergoing thoracic surgery. In vivo responsiveness was determined by administration of inhalations of doubling concentrations of methacholine. Results were expressed as the provocation concentration (PC) causing a decrease in forced expiratory volume in one second of 20% (PC20FEV1), specific airway conductance of 35% (PC35SGaw), and maximal expiratory flow at 35% vital capacity, measured for the partial (V35(p)) and complete (V35(c)) flow volume curves, of 35% (PC35V35(p); PC35V35(c)). In vitro airway smooth muscle sensitivity was determined from specimens obtained at thoracotomy. Log dose-response curves to methacholine were constructed and the concentration causing a 50% maximum contraction (EC50) was derived. There were differences between patients for both in vivo airway responsiveness and in vitro smooth muscle sensitivity to methacholine. There were no significant relationships between the in vivo and in vitro measurements. The results suggest that factors other than solely the sensitivity of smooth muscle must determine in vivo airway responsiveness to methacholine.


Designer DNA architecture offers precise and multivalent spatial pattern-recognition for viral sensing and inhibition.
DNA, when folded into nanostructures with a specific shape, is capable of spacing and arranging binding sites into a complex geometric pattern with nanometre precision. Here we demonstrate a designer DNA nanostructure that can act as a template to display multiple binding motifs with precise spatial pattern-recognition properties, and that this approach can confer exceptional sensing and potent viral inhibitory capabilities. A star-shaped DNA architecture, carrying five molecular beacon-like motifs, was constructed to display ten dengue envelope protein domain III (ED3)-targeting aptamers into a two-dimensional pattern precisely matching the spatial arrangement of ED3 clusters on the dengue (DENV) viral surface. The resulting multivalent interactions provide high DENV-binding avidity. We show that this structure is a potent viral inhibitor and that it can act as a sensor by including a fluorescent output to report binding. Our molecular-platform design strategy could be adapted to detect and combat other disease-causing pathogens by generating the requisite ligand patterns on customized DNA nanoarchitectures.


The berberis story: Berberis vulgaris in therapeutics.
Barberry has played a prominent role in herbal healing for more than 2,500 years. Berberis vulgaris is a common garden bush, native to Europe and the British Isles, naturalized in North America, seems to have history as old as human race. Anthropologists believe in a ritual practice or sacred object, especially by Native Americans that it works as a supernatural power or as preventive or remedy of illness. It is a deciduous shrub having yellow flowers and scarlet colored fruit in the form of berries. Twenty two alkaloids have been reported so far from root, stem leaves and fruit of this plant, which are of medicinal importance. As a herbal remedy it has no match in serving human race since ancient times. It is the most widely used drug in Homeopathic system of medicine for kidney pain and for removal of kidney stones. In this article, we present countless blessings of nature encountered through this herb which are worthy of recording.


Gendered traditional agroecological knowledge in agri-food systems: a systematic review.
Traditional agroecological knowledge (i.e. TAeK) is gaining recognition for its potential contribution to climate change adaptation in food systems, ecosystems restoration and food insecurity. Despite the existing literature on Traditional Ecological Knowledge and its nexus with food security, how gender critically influences the distribution of such knowledge within agri-food systems has not yet been systematically analysed. In this regard, this systematic review attempts to answer four questions: 1) How does the literature on gender and TAeK in agri-food systems evolved temporally, geographically and in different agroecosystems? 2) How are gender and intersectionality mainly approached by such literature? 3) How do the articles address gendered dimensions in TAeK within the agri-food system activities? 4) What are the main drivers of change that influence TAeK and adaptive responses? The results show the gendered nature of TAeK in relation to food production, processing, and conservation activities, and how these activities are linked to tasks and activities, gender-specific knowledge, and spaces where gender discrimination is reproduced. The review also identifies elements that delimit and/or take part of the development of TAeK, such as gendered access to resources, gendered institutions, and the identification of the main drivers of change and impacts of TAeK erosion and biodiversity loss. These results are discussed in terms of power relations that interact with sociocultural norms and practices according to the specific geographical context and agroecosystem.


Increases in alpha oscillatory power reflect an active retinotopic mechanism for distracter suppression during sustained visuospatial attention.
Human electrophysiological (EEG) studies have demonstrated the involvement of alpha band (8- to 14-Hz) oscillations in the anticipatory biasing of attention. In the context of visual spatial attention within bilateral stimulus arrays, alpha has exhibited greater amplitude over parietooccipital cortex contralateral to the hemifield required to be ignored, relative to that measured when the same hemifield is to be attended. Whether this differential effect arises solely from alpha desynchronization (decreases) over the "attending" hemisphere, from synchronization (increases) over the "ignoring" hemisphere, or both, has not been fully resolved. This is because of the confounding effect of externally evoked desynchronization that occurs involuntarily in response to visual cues. Here, bilateral flickering stimuli were presented simultaneously and continuously over entire trial blocks, such that externally evoked alpha desynchronization is equated in precue baseline and postcue intervals. Equivalent random letter sequences were superimposed on the left and right flicker stimuli. Subjects were required to count the presentations of the target letter "X" at the cued hemifield over an 8-s period and ignore the sequence in the opposite hemifield. The data showed significant increases in alpha power over the ignoring hemisphere relative to the precue baseline, observable for both cue directions. A strong attentional bias necessitated by the subjective difficulty in gating the distracting letter sequence is reflected in a large effect size of 2.1 (eta2 = 0.82), measured from the attention x hemisphere interaction. This strongly suggests that alpha synchronization reflects an active attentional suppression mechanism, rather than a passive one reflecting "idling" circuits.


Cannabidiol acts as molecular switch in innate immune cells to promote the biosynthesis of inflammation-resolving lipid mediators.
Cannabinoids are phytochemicals from cannabis with anti-inflammatory actions in immune cells. Lipid mediators (LM), produced from polyunsaturated fatty acids (PUFA), are potent regulators of the immune response and impact all stages of inflammation. How cannabinoids influence LM biosynthetic networks is unknown. Here, we reveal cannabidiol (CBD) as a potent LM class-switching agent that stimulates the production of specialized pro-resolving mediators (SPMs) but suppresses pro-inflammatory eicosanoid biosynthesis. Detailed metabololipidomics analysis in human monocyte-derived macrophages showed that CBD (i) upregulates exotoxin-stimulated generation of SPMs, (ii) suppresses 5-lipoxygenase (LOX)-mediated leukotriene production, and (iii) strongly induces SPM and 12/15-LOX product formation in resting cells by stimulation of phospholipase A2-dependent PUFA release and through Ca2+-independent, allosteric 15-LOX-1 activation. Finally, in zymosan-induced murine peritonitis, CBD increased SPM and 12/15-LOX products and suppressed pro-inflammatory eicosanoid levels in vivo. Switching eicosanoid to SPM production is a plausible mode of action of CBD and a promising inflammation-resolving strategy.


Tissue factor expression in neutrophil extracellular traps and neutrophil derived microparticles in antineutrophil cytoplasmic antibody associated vasculitis may promote thromboinflammation and the thrombophilic state associated with the disease.
Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is characterised by neutrophil activation. An elevated prevalence of venous thromboembolic events has been reported in AAV. Because of the critical role of neutrophils in inflammation associated thrombosis, we asked whether neutrophil tissue factor (TF) may be implicated in the thrombotic diathesis in AAV. Neutrophils from four patients and sera from 17 patients with ANCA associated vasculitis with active disease and remission were studied. TF expression was assessed by immunoblotting and confocal microscopy. Circulating DNA levels were evaluated. TF expressing microparticles (MPs) were measured by flow cytometry and thrombin-antithrombin complex levels by ELISA. Peripheral blood neutrophils from four patients with active disease expressed elevated TF levels and released TF expressing neutrophil extracellular traps (NETs) and MPs. TF positive NETs were released by neutrophils isolated from the bronchoalveolar lavage and were detected in nasal and renal biopsy specimens. Elevated levels of circulating DNA and TF expressing neutrophil derived MPs were further observed in sera from patients with active disease. Induction of remission attenuated the aforementioned effects. Control neutrophils treated with sera from patients with active disease released TF bearing NETs and MPs which were abolished after IgG depletion. Treatment of control neutrophils with isolated IgG from sera from patients with active disease also resulted in the release of TF bearing NETs. TF implication in MP dependent thrombin generation was demonstrated by antibody neutralisation studies. Expression of TF in NETs and neutrophil derived MPs proposes a novel mechanism for the induction of thrombosis and inflammation in active AAV.


Ultraflexible Neural Electrodes for Long-Lasting Intracortical Recording.
Implanted electrodes provide one of the most important neurotechniques for fundamental and translational neurosciences by permitting time-resolved electrical detection of individual neurons in vivo. However, conventional rigid electrodes typically cannot provide stable, long-lasting recordings. Numerous interwoven biotic and abiotic factors at the tissue-electrode interface lead to short- and long-term instability of the recording performance. Making neural electrodes flexible provides a promising approach to mitigate these challenges on the implants and at the tissue-electrode interface. Here we review the recent progress of ultraflexible neural electrodes and discuss the engineering principles, the material properties, and the implantation strategies to achieve stable tissue-electrode interface and reliable unit recordings in living brains.


Investigation of the Nanocrystal CoS2 Embedded in 3D Honeycomb-like Graphitic Carbon with a Synergistic Effect for High-Performance Lithium Sulfur Batteries.
Lithium sulfur (Li-S) batteries can offer great opportunities for the next-generation energy storage systems with tremendous energy density. However, challenges still exist in practical Li-S batteries including low sulfur utilization, and poor cycling stability and rate capability. Herein, we propose a novel hybrid catalyst structure by in situ implanting nanocrystal CoS2 in three-dimensional honeycomb-like hierarchical porous graphitic carbon (HPGC) for high-performance Li-S batteries. A unique synergistic absorption-catalysis-functional effect is demonstrated by comprehensive experimental and theoretical analysis: strong physical and chemical co-absorption effects are originated from the large quantity of microporous HPGC and the polar surface of metallic CoS2; the introduced nanocrystal CoS2 with a large specific area can impose an exceptional catalytic effect on the liquid-liquid, solid-liquid, and solid-solid phase redox reactions in Li-S batteries; the reaction dynamics are further guaranteed by the multifunctional properties of the HPGC backbone, including the capabilities in polysulfide sustention, reaction product transportation, electrolyte compensation, and efficiency in assisting diverse electrochemical reaction dynamics. In this way, our results not only develop a novel CoS2@HPGC structure, but also provide fundamental understanding on the catalytic dynamics during each reaction process. Moreover, we further propose the necessity and philosophy of the rational design of catalysts' special structure, which can fulfill the functional dynamics requirements of Li-S batteries, and can be promoted to other Li-S-related cathode design and composite catalytic structure design.


Identification and functional characterization of Epstein-Barr virus DNA polymerase by in vitro transcription-translation of a cloned gene.
In order to identify the gene encoding the Epstein-Barr virus (EBV) DNA polymerase, a portion of the BamHI-A fragment containing the fifth leftward open reading frame (BALF5) of the EBV genome was cloned into SP6 and T7 promoter-containing vectors for in vitro transcription-translation. The RNA synthesized in vitro was used to program rabbit reticulocyte lysates, which were analyzed for the synthesis of the putative polymerase polypeptide (110 kDa) and assayed directly for EBV DNA polymerase activity. The polypeptide synthesized by the full-length BALF5 genomic fragment had a molecular mass of 110 kDa. 5'-truncated BALF5 with the first and second ATGs deleted produced 95- and 83-kDa polypeptides, respectively. All three translation products were enzymatically active and displayed resistance to high salt concentrations. The identity of the largest polypeptide as the viral polymerase was established by (i) immunoprecipitation with EBV-positive sera from patients with nasopharyngeal carcinoma and by a rabbit polyclonal antiserum prepared with a synthetic peptide derived from the DNA sequence of BALF5; (ii) identification of a polypeptide of identical size (110 kDa) immunoprecipitated from superinfected Raji cell extracts by these antibodies; and (iii) salt-resistant enzymatic activity which was neutralized by the rabbit EBV antiserum. Thus, BALF5 encodes a functional polymerase identical to that induced in superinfected Raji cells.


In vitro functional effects of XPC gene rare variants from bladder cancer patients.
The XPC gene is involved in repair of bulky DNA adducts formed by carcinogenic metabolites and oxidative DNA damage, both known bladder cancer risk factors. Single nucleotide polymorphisms (SNPs) in XPC have been associated with increased bladder cancer risk. Recently, rarer genetic variants have been identified but it is difficult to ascertain which are of functional importance. During a mutation screen of XPC in DNA from 33 bladder tumour samples and matched blood samples, we identified five novel variants in the patients' germ line DNA. In a case-control study of 771 bladder cancer cases and 800 controls, c.905T>C (Phe302Ser), c.1177C>T (Arg393Trp), c.*156G>A [3' untranslated region (UTR)] and c.2251-37C>A (in an intronic C>G SNP site) were found to be rare variants, with a combined odds ratio of 3.1 (95% confidence interval 1.0-9.8, P=0.048) for carriage of one variant. The fifth variant was a 2% minor allele frequency SNP not associated with bladder cancer. The two non-synonymous coding variants were predicted to have functional effects using analytical algorithms; a reduced recruitment of GFP-tagged XPC plasmids containing either c.905T>C or c.1177C>T to sites of 408 nm wavelength laser-induced oxidative DNA damage was found in vitro. c.*156G>A appeared to be associated with reduced messenger RNA stability in an in vitro plasmid-based assay. Although the laser microbeam assay is relevant to a range of DNA repair genes, our 3' UTR assay based on Green fluorescent protein(GFP) has widespread applicability and could be used to assess any gene. These assays may be useful in determining which rare variants are functional, prior to large genotyping efforts.


Ghost-tree: creating hybrid-gene phylogenetic trees for diversity analyses.
Fungi play critical roles in many ecosystems, cause serious diseases in plants and animals, and pose significant threats to human health and structural integrity problems in built environments. While most fungal diversity remains unknown, the development of PCR primers for the internal transcribed spacer (ITS) combined with next-generation sequencing has substantially improved our ability to profile fungal microbial diversity. Although the high sequence variability in the ITS region facilitates more accurate species identification, it also makes multiple sequence alignment and phylogenetic analysis unreliable across evolutionarily distant fungi because the sequences are hard to align accurately. To address this issue, we created ghost-tree, a bioinformatics tool that integrates sequence data from two genetic markers into a single phylogenetic tree that can be used for diversity analyses. Our approach starts with a "foundation" phylogeny based on one genetic marker whose sequences can be aligned across organisms spanning divergent taxonomic groups (e.g., fungal families). Then, "extension" phylogenies are built for more closely related organisms (e.g., fungal species or strains) using a second more rapidly evolving genetic marker. These smaller phylogenies are then grafted onto the foundation tree by mapping taxonomic names such that each corresponding foundation-tree tip would branch into its new "extension tree" child. We applied ghost-tree to graft fungal extension phylogenies derived from ITS sequences onto a foundation phylogeny derived from fungal 18S sequences. Our analysis of simulated and real fungal ITS data sets found that phylogenetic distances between fungal communities computed using ghost-tree phylogenies explained significantly more variance than non-phylogenetic distances. The phylogenetic metrics also improved our ability to distinguish small differences (effect sizes) between microbial communities, though results were similar to non-phylogenetic methods for larger effect sizes. The Silva/UNITE-based ghost tree presented here can be easily integrated into existing fungal analysis pipelines to enhance the resolution of fungal community differences and improve understanding of these communities in built environments. The ghost-tree software package can also be used to develop phylogenetic trees for other marker gene sets that afford different taxonomic resolution, or for bridging genome trees with amplicon trees. ghost-tree is pip-installable. All source code, documentation, and test code are available under the BSD license at https://github.com/JTFouquier/ghost-tree .


Can the MOLES acronym and scoring system improve the management of patients with melanocytic choroidal tumours?
It can be difficult for practitioners to determine the likelihood of malignancy in melanocytic choroidal tumours. This author has therefore devised the MOLES acronym to highlight the most informative clinical features, which comprise mushroom shape, orange pigment, large size, enlargement, and subretinal fluid. Each of these is scored 0 if absent, 1 if subtle or uncertain, and 2 if present. Tumours are categorised as 'common naevus', 'low-risk naevus', 'high-risk naevus' and 'probable melanoma' according to whether the sum of these five scores is 0, 1, 2 or 3 or more, respectively. Tentative recommendations, subject to future studies, include: review of 'common naevi' by a community optometrist whenever the patient attends for another reason, such as a two-yearly 'check-up' (i.e., 'self-care'); non-urgent referral of patients with 'low-risk naevi' or 'high-risk naevi' to an ophthalmologist to plan long-term surveillance (i.e., determining the frequency of assessments and whether these should be undertaken by an ophthalmologist or a community optometrist); and urgent referral of patients with a MOLES score >2 (i.e., 'probable melanoma') to an ophthalmologist for immediate referral to an ocular oncologist if a suspicion of malignancy is confirmed. The MOLES system does not require assessment of internal acoustic reflectivity by ultrasonography. MOLES scores correlate well with diagnosis of choroidal naevi and melanomas by ocular oncologists; however, further evaluation of this aid in routine optometric practice and other situations is needed. MOLES should prevent unnecessary referral of patients with naevi for second opinion and non-essential monitoring of these patients at hospital eye services.


International Collaboration for the Epidemiology of eGFR in Low and Middle Income Populations - Rationale and core protocol for the Disadvantaged Populations eGFR Epidemiology Study (DEGREE).
There is an increasing recognition of epidemics of primarily tubular-interstitial chronic kidney disease (CKD) clustering in agricultural communities in low- and middle-income countries (LMICs). Although it is currently unclear whether there is a unified underlying aetiology, these conditions have been collectively termed CKD of undetermined cause (CKDu). CKDu is estimated to have led to the premature deaths of tens to hundreds of thousands of young men and women over the last 2 decades. Thus, there is an urgent need to understand the aetiology and pathophysiology of these condition (s). International comparisons have provided the first steps in understanding many chronic diseases, but such comparisons rely on the availability of standardised tools to estimate disease prevalence. This is a particular problem with CKD, since the disease is asymptomatic until the late stages, and the biases inherent in the methods used to estimate the glomerular filtration rate (GFR) in population studies are highly variable across populations. We therefore propose a simple standardised protocol to estimate the distribution of GFR in LMIC populations - The Disadvantaged Populations eGFR Epidemiology (DEGREE) Study. This involves the quantification of renal function in a representative adult population-based sample and a requirement for standardisation of serum creatinine measurements, along with storage of samples for future measurements of cystatin C and ascertainment of estimates of body composition, in order to obtain valid comparisons of estimated GFR (eGFR) within and between populations. The methodology we present is potentially applicable anywhere, but our particular focus is on disadvantaged populations in LMICs, since these appear to be most susceptible to CKDu. Although the protocol could also be used in specific groups (e.g. occupational groups, thought to be at excess risk of CKDu) the primary aim of the DEGREE project is characterise the population distribution of eGFR in multiple regions so that international comparisons can be performed. It is only with a standardised approach that it will be possible to estimate the scale of, and variation in, impaired kidney function between affected areas. These data should then provide insights into important social, demographic and environmental risk factors for this increasingly recognised disease.


Creating the best workplace on earth.
No organization can fulfill every hope and desire of its employees, so it helps to know which matter most to people. Goffee and Jones have identified the six most essential imperatives for creating an ideal work environment. Their insights come from surveys and interviews of hundreds of executives from all over the world. Few organizations embody all six attributes of the dream organization, many are difficult to achieve, and some even conflict with one another. But they nonetheless stand as an agenda for executives who wish to create the most productive, most rewarding workplace imaginable. Agenda 1. Let people be themselves. 2. Unleash the flow of information. 3. Magnify people's strengths. 4. Stand for more than shareholder value. 5. Show how the daily work makes sense. 6. Have rules people can believe in. This list contains no surprises, but implementing the elements is no easy task. Almost all of them require leaders to carefully balance competing interests and to reallocate their time and attention. Companies like Arup, LVMH, Waitrose, and even McDonald's are doing it to varying degrees. Your challenge is to match-and then to exceed-what they have managed to accomplish.


Predicting the stroke patient's ability to live independently.
The objective of this paper is to identify those variables that best predict a stroke patient's ability to live independently following his/her discharge from medical rehabilitation. The paper draws heavily on a formal research model grounded in independent living (IL) theory. Independent living is defined and operationalized as (1) the patient's ability to live in a nonrestrictive environment and (2) the patient's ability to live productively--not only in terms of gainful employment but also in terms of other contributions to community and family life. The main data source for the study is an extensive computer file of 84 stroke patients discharged from 8 medical rehabilitation centers. The multivariate statistical analysis indicates that 56 to 80 percent of the variance in a patient's ability to live independently can be explained or predicted mainly by the patient's marital status, age, Barthel score, communication impairments, and the ability to get into a motor vehicle. The paper concludes by discussing the implications of the findings for medical rehabilitation and public policy.


Bond strength of different adhesive systems to dental hard tissues.
This study compared the shear bond strengths of different adhesive systems to enamel and dentin of different depths. The adhesive systems used were: Single Bond one-bottle total-etch; AQ Bond one-step self-etching, Clearfil SE Bond two-step self-etching and Tyrian SPE/One-step Plus two-step self-etching. Eighty extracted non-carious human mandibular molars were mounted in self-curing resin and the occlusal surfaces were ground with a mechanical grinder to obtain flat occlusal enamel surfaces. After applying the adhesive systems, a plastic tube was attached to the enamel surfaces. The tube was filled with a universal hybrid resin composite, which was then polymerized. The specimens were stored in water at 37 degrees C for 24 hours. Shear bond testing was carried out using an Instron Universal testing machine with a crosshead speed of 1 mm/minute. The occlusal enamel of the 80 teeth was removed to determine the bond strengths of the adhesives to superficial dentin. To obtain deep dentin, the same teeth were ground deep towards the pulp, with the remaining dentin thickness approximately 0.7 mm. The adhesives and restorative material were then applied to the prepared dentin surfaces following the methodology described above. For occlusal enamel surfaces, the bond strength of Single Bond was significantly higher than the other adhesives. Single Bond, Clearfil SE Bond and Tyrian SPE/One-step Plus performed equally when bonded to superficial dentin; the lowest bond strength was obtained with AQ Bond. On deep dentin, the highest bond strengths were obtained with Clearfil SE Bond. For each adhesive system, shear bond strength to enamel was statistically higher than it was to either superficial or deep dentin. There were no significant differences between shear bond strengths to superficial versus deep dentin, regardless of adhesive.


A Machine Learning Based Approach to de novo Sequencing of Glycans from Tandem Mass Spectrometry Spectrum.
Recently, glycomics has been actively studied and various technologies for glycomics have been rapidly developed. Currently, tandem mass spectrometry (MS/MS) is one of the key experimental tools for identification of structures of oligosaccharides. MS/MS can observe MS/MS peaks of fragmented glycan ions including cross-ring ions resulting from internal cleavages, which provide valuable information to infer glycan structures. Thus, the aim of de novo sequencing of glycans is to find the most probable assignments of observed MS/MS peaks to glycan substructures without databases. However, there are few satisfiable algorithms for glycan de novo sequencing from MS/MS spectra. We present a machine learning based approach to de novo sequencing of glycans from MS/MS spectrum. First, we build a suitable model for the fragmentation of glycans including cross-ring ions, and implement a solver that employs Lagrangian relaxation with a dynamic programming technique. Then, to optimize scores for the algorithm, we introduce a machine learning technique called structured support vector machines that enable us to learn parameters including scores for cross-ring ions from training data, i.e., known glycan mass spectra. Furthermore, we implement additional constraints for core structures of well-known glycan types including N-linked glycans and O-linked glycans. This enables us to predict more accurate glycan structures if the glycan type of given spectra is known. Computational experiments show that our algorithm performs accurate de novo sequencing of glycans. The implementation of our algorithm and the datasets are available at http://glyfon.dna.bio.keio.ac.jp/.


Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271.
The question of whether tumorigenic cancer stem cells exist in human melanomas has arisen in the last few years. Here we show that in melanomas, tumour stem cells (MTSCs, for melanoma tumour stem cells) can be isolated prospectively as a highly enriched CD271(+) MTSC population using a process that maximizes viable cell transplantation. The tumours sampled in this study were taken from a broad spectrum of sites and stages. High-viability cells isolated by fluorescence-activated cell sorting and re-suspended in a matrigel vehicle were implanted into T-, B- and natural-killer-deficient Rag2(-/-)gammac(-/-) mice. The CD271(+) subset of cells was the tumour-initiating population in 90% (nine out of ten) of melanomas tested. Transplantation of isolated CD271(+) melanoma cells into engrafted human skin or bone in Rag2(-/-)gammac(-/-) mice resulted in melanoma; however, melanoma did not develop after transplantation of isolated CD271(-) cells. We also show that in mice, tumours derived from transplanted human CD271(+) melanoma cells were capable of metastatsis in vivo. CD271(+) melanoma cells lacked expression of TYR, MART1 and MAGE in 86%, 69% and 68% of melanoma patients, respectively, which helps to explain why T-cell therapies directed at these antigens usually result in only temporary tumour shrinkage.


Photogrammetry-based stereoscopic optode registration method for functional near-infrared spectroscopy.
Functional near-infrared spectroscopy (fNIRS) is an emerging brain imaging technique due to its small size, low cost, minimum scanning sonic noise, and portability. Unfortunately, because this technique does not provide neuroanatomical information to accompany the functional data, its data interpretation remains a persistent challenge in fNIRS brain imaging applications. The two most popular approaches for fNIRS anatomical registration are magnetic resonance imaging (MRI) and three-dimensional (3-D) digitization. MRI scanning yields high-precision registration but reduces the cost-effectiveness and accessibility of fNIRS imaging. Alternatively, the low cost and portable 3-D digitizers are affected by magnetic properties of ambient metal objects, including participant clothing, testing equipment, medical implants, and so forth. To overcome these obstacles and provide accessible and reliable neuroanatomical registration for fNIRS imaging, we developed and explored a photogrammetry optode registration (POR) method. The POR method uses a consumer-grade camera to reconstruct a 3-D image of the fNIRS optode-set, including light emitters and detectors, on a participant's head. This reconstruction process uses a linear-time incremental structure from motion (LTI-SfM) algorithm, based on 100 to 150 digital photos. The POR method then aligns the reconstructed image with an anatomical template of the brain. To validate this method, we tested 22 adult and 19 child participants using the POR method and MRI imaging. The results comparisons suggest on average 55% and 46% overlap across all data channel measurements registered by the two methods in adult and children, respectively. Importantly, this overlap reached 65% and 60% in only the frontal channels. These results suggested that the mismatch in registration was partially due to higher variation in backward optode placement rather than the registration efficacy. Therefore, the photo-based registration method can offer an accessible and reliable approach to neuroanatomical registration of fNIRS as well as other surface-based neuroimaging and neuromodulation methods.


Image and performance enhancing drug use among men who have sex with men and women who have sex with women in the UK.
The use of image and performance enhancing drugs (IPEDs) among men who have sex with men (MSM) and women who have sex with women (WSW) is rarely studied, with most of this research focused on anabolic androgenic steroid use among MSM. To address this gap, the extent of recent IPED use and the associated factors are explored in a community-recruited sample of MSM and WSW METHODS: Data from the UK LGBT Sex and Lifestyles Survey was used, which recruited through social-media advertising and community organisations (April-June 2018). Participants were asked if they had taken any IPEDs (e.g. anabolic steroids, growth hormone, hCG, Melanotan, non-prescribed diet pills) in the past 12 months. Factors associated with recent (in past 12 months) IPED use among MSM and WSW were investigated using stepwise binary logistic regression. 1,658 MSM and 1,507 WSW were included in the analysis. Among MSM, 3.4% (n = 57) had recently taken IPEDs, 60% of those taking IPEDs had used psychoactive drugs. In the multivariable analysis, IPED use among MSM was associated with psychoactive drug use, Viagra use, higher body dissatisfaction, and lower sexual satisfaction. Among WSW, 4.1% (n = 62) had recently taken IPEDs, and 50% of those taking IPEDs had used psychoactive drugs. In the multivariable analysis, IPED use among WSW was associated with being aged 45 years and over, recent STI diagnosis, recent sexual contact without consent, and higher body dissatisfaction. IPED use was reported by around 1-in-25 MSM and WSW, and was associated with a number of health and psychological problems. Research to better understand the drivers and impacts of IPED use among MSM and WSW, and how this compares to use among heterosexual people is needed.


Artemisia dracunculus L. (tarragon): a critical review of its traditional use, chemical composition, pharmacology, and safety.
Artemisia dracunculus L. (tarragon) has a long history of use as a spice and remedy. Two well-described "cultivars" (Russian and French) are used widely and differ in ploidy level, morphology, and chemistry. Key biologically active secondary metabolites are essential oils (0.15-3.1%), coumarins (>1%), flavonoids, and phenolcarbonic acids. In vivo studies mainly in rodents, particularly from Russian sources, highlight potential anti-inflammatory, hepatoprotective, and antihyperglycemic effects. Despite concerns about the toxic effects of two of its main constituents, estragole (up to 82%) and methyleugenol (up to 39%), no acute toxicity or mutagenic activity has been reported at doses relevant for human consumption. Water extracts of A. dracunculus contain very low amounts of estragole and methyleugenol and, therefore, are considered to pose a very limited risk. Overall, a stronger focus on clinical studies and precise taxonomic and phytochemical definition of the source material will be essential for future research efforts.


Chromosomal abnormality rates at amniocentesis and in live-born infants.
Regression-smoothed maternal age-specific rates of six different categories of cytogenetic abnormalities in recent large-scale prenatal cytogenetic studies were multiplied by independently derived fetal selection coefficients--factors that adjust for the excess likelihood of spontaneous loss of cytogenetically abnormal fetuses--to obtain estimated maternal age-specific rates of these categories of cytogenetic abnormalities in live-born infants. The derived rates apply to women whose only risk factor is advanced maternal age. The categories analyzed were 47,+21 (Down's syndrome), 47,+18 (Edwards' syndrome), 47,+13 (Patau's syndrome), 47,XXY (Klinefelter's syndrome), 47,XXX, and the group of other clinically significant abnormalities considered collectively. The rate of all clinically significant abnormalities considered together derived in this study was about five per 1,000 at age 35 years, 15 per 1,000 at age 40 years, and 50 per 1,000 at age 45 years.


Rapid changes in seed dispersal traits may modify plant responses to global change.
When climatic or environmental conditions change, plant populations must either adapt to these new conditions, or track their niche via seed dispersal. Adaptation of plants to different abiotic environments has mostly been discussed with respect to physiological and demographic parameters that allow local persistence. However, rapid modifications in response to changing environmental conditions can also affect seed dispersal, both via plant traits and via their dispersal agents. Studying such changes empirically is challenging, due to the high variability in dispersal success, resulting from environmental heterogeneity, and substantial phenotypic variability of dispersal-related traits of seeds and their dispersers. The exact mechanisms that drive rapid changes are often not well understood, but the ecological implications of these processes are essential determinants of dispersal success, and deserve more attention from ecologists, especially in the context of adaptation to global change. We outline the evidence for rapid changes in seed dispersal traits by discussing variability due to plasticity or genetics broadly, and describe the specific traits and biological systems in which variability in dispersal is being studied, before discussing some of the potential underlying mechanisms. We then address future research needs and propose a simulation model that incorporates phenotypic plasticity in seed dispersal. We close with a call to action and encourage ecologists and biologist to embrace the challenge of better understanding rapid changes in seed dispersal and their consequences for the reaction of plant populations to global change.


The Photovoltaic Heat Island Effect: Larger solar power plants increase local temperatures.
While photovoltaic (PV) renewable energy production has surged, concerns remain about whether or not PV power plants induce a "heat island" (PVHI) effect, much like the increase in ambient temperatures relative to wildlands generates an Urban Heat Island effect in cities. Transitions to PV plants alter the way that incoming energy is reflected back to the atmosphere or absorbed, stored, and reradiated because PV plants change the albedo, vegetation, and structure of the terrain. Prior work on the PVHI has been mostly theoretical or based upon simulated models. Furthermore, past empirical work has been limited in scope to a single biome. Because there are still large uncertainties surrounding the potential for a PHVI effect, we examined the PVHI empirically with experiments that spanned three biomes. We found temperatures over a PV plant were regularly 3-4 °C warmer than wildlands at night, which is in direct contrast to other studies based on models that suggested that PV systems should decrease ambient temperatures. Deducing the underlying cause and scale of the PVHI effect and identifying mitigation strategies are key in supporting decision-making regarding PV development, particularly in semiarid landscapes, which are among the most likely for large-scale PV installations.


Cost effectiveness of internet-based cognitive behaviour therapy and behavioural stress management for severe health anxiety.
Internet-delivered exposure-based cognitive behaviour therapy (ICBT) has been shown to be effective in the treatment of severe health anxiety. The health economic effects of the treatment have, however, been insufficiently studied and no prior study has investigated the effect of ICBT compared with an active psychological treatment. The aim of the present study was to investigate the cost effectiveness of ICBT compared with internet-delivered behavioural stress management (IBSM) for adults with severe health anxiety defined as Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) hypochondriasis. ICBT was hypothesised to be the more cost-effective treatment. This was a cost-effectiveness study within the context of a randomised controlled trial conducted in a primary care/university setting. Participants from all of Sweden could apply to participate. Self-referred adults (N=158) with a principal diagnosis of DSM-IV hypochondriasis, of whom 151 (96%) provided baseline and post-treatment data. ICBT or IBSM for 12 weeks. The primary outcome was the Health Anxiety Inventory. The secondary outcome was the EQ-5D. Other secondary measures were used in the main outcome study but were not relevant for the present health economic analysis. Both treatments led to significant reductions in gross total costs, costs of healthcare visits, direct non-medical costs and costs of domestic work cutback (p=0.000-0.035). The incremental cost-effectiveness ratio (ICER) indicated that the cost of one additional case of clinically significant improvement in ICBT compared with IBSM was $2214. The cost-utility ICER, that is, the cost of one additional quality-adjusted life year, was estimated to be $10,000. ICBT is a cost-effective treatment compared with IBSM and treatment costs are offset by societal net cost reductions in a short time. A cost-benefit analysis speaks for ICBT to play an important role in increasing access to effective treatment for severe health anxiety. NCT01673035; Results.


Interventions for promoting physical activity in people with neuromuscular disease.
The World Health Organization (WHO) recommends that people of all ages take regular and adequate physical activity. If unable to meet the recommendations due to health conditions, international guidance advises being as physically active as possible. Evidence from community interventions of physical activity indicate that people living with medical conditions are sometimes excluded from participation in studies. In this review, we considered the effects of activity-promoting interventions on physical activity and well-being in studies, as well as any adverse events experienced by participants living with inherited or acquired neuromuscular diseases (NMDs). OBJECTIVES: To assess the effects of interventions designed to promote physical activity in people with NMD compared with no intervention or alternative interventions. On 30 April 2020, we searched Cochrane Neuromuscular Specialised Register, CENTRAL, Embase, MEDLINE, and ClinicalTrials.Gov. WHO ICTRP was not accessible at the time. We considered randomised or quasi-randomised trials, including cross-over trials, of interventions designed to promote physical activity in people with NMD compared to no intervention or alternative interventions. We specifically included studies that reported physical activity as an outcome measure. Our main focus was studies in which promoting physical activity was a stated aim but we also included studies in which physical activity was assessed as a secondary or exploratory outcome. We used standard Cochrane procedures. The review included 13 studies (795 randomised participants from 12 studies; number of participants unclear in one study) of different interventions to promote physical activity. Most studies randomised a minority of invited participants. No study involved children or adolescents and nine studies reported minimal entry criteria for walking. Participants had one of nine inherited or acquired NMDs. Types of intervention included structured physical activity support, exercise support (as a specific form of physical activity), and behaviour change support that included physical activity or exercise. Only one included study clearly reported that the aim of intervention was to increase physical activity. Other studies reported or planned to analyse the effects of intervention on physical activity as a secondary or exploratory outcome measure. Six studies did not report results for physical activity outcomes, or the data were not usable. We judged 10 of the 13 included studies at high or unclear risk of bias from incomplete physical activity outcome reporting. We did not perform a meta-analysis for any comparison because of differences in interventions and in usual care. We also found considerable variation in how studies reported physical activity as an outcome measure. The studies that reported physical activity measurement did not always clearly report intention-to-treat (ITT) analysis or whether final assessments occurred during or after intervention. Based on prespecified measures, we included three comparisons in our summary of findings. A physical activity programme (weight-bearing) compared to no physical activity programme One study involved adults with diabetic peripheral neuropathy (DPN) and reported weekly duration of walking during and at the end of a one-year intervention using a StepWatch ankle accelerometer. Based on the point estimate and low-certainty evidence, intervention may have led to an important increase in physical activity per week; however, the 95% confidence interval (CI) included the possibility of no difference or an effect in either direction at three months (mean difference (MD) 34 minutes per week, 95% CI -92.19 to 160.19; 69 participants), six months (MD 68 minutes per week, 95% CI -55.35 to 191.35; 74 participants), and 12 months (MD 49 minutes per week, 95% CI -75.73 to 173.73; 70 participants). Study-reported effect estimates for foot lesions and full-thickness ulcers also included the possibility of no difference, a higher, or lower risk with intervention. A sensor-based, interactive exercise programme compared to no sensor-based, interactive exercise programme One study involved adults with DPN and reported duration of walking over 48 hours at the end of four weeks' intervention using a t-shirt embedded PAMSys sensor. It was not possible to draw conclusions about the effectiveness of the intervention from the very low-certainty evidence (MD -0.64 hours per 48 hours, 95% CI -2.42 to 1.13; 25 participants). We were also unable to draw conclusions about impact on the Physical Component Score (PCS) for quality of life (MD 0.24 points, 95% CI -5.98 to 6.46; 35 participants; very low-certainty evidence), although intervention may have made little or no difference to the Mental Component Score (MCS) for quality of life (MD 5.10 points, 95% CI -0.58 to 10.78; 35 participants; low-certainty evidence). A functional exercise programme compared to a stretching exercise programme One study involved adults with spinal and bulbar muscular atrophy and reported a daily physical activity count at the end of 12 weeks' intervention using an Actical accelerometer. It was not possible to draw conclusions about the effectiveness of either intervention (requiring compliance) due to low-certainty evidence and unconfirmed measurement units (MD -8701, 95% CI -38,293.30 to 20,891.30; 43 participants). Functional exercise may have made little or no difference to quality of life compared to stretching (PCS: MD -1.10 points, 95% CI -5.22 to 3.02; MCS: MD -1.10 points, 95% CI -6.79 to 4.59; 49 participants; low-certainty evidence). Although studies reported adverse events incompletely, we found no evidence of supported activity increasing the risk of serious adverse events. We found a lack of evidence relating to children, adolescents, and non-ambulant people of any age. Many people living with NMD did not meet randomised controlled trial eligibility criteria. There was variation in the components of supported activity intervention and usual care, such as physical therapy provision. We identified variation among studies in how physical activity was monitored, analysed, and reported. We remain uncertain of the effectiveness of promotional intervention for physical activity and its impact on quality of life and adverse events. More information is needed on the ITT population, as well as more complete reporting of outcomes. While there may be no single objective measure of physical activity, the study of qualitative and dichotomous change in self-reported overall physical activity might offer a pragmatic approach to capturing important change at an individual and population level.


Fulminant Brain Atrophy and Vasculitis on Vessel-Wall Imaging in Neuropsychiatric Lupus: Case Report and Literature Review.
Brain atrophy, typically slowly progressive, is a hallmark of neuropsychiatric (NP) systemic lupus erythematosus (SLE). In this article, we report a case of a young female patient with previously diagnosed SLE, without known NPSLE, with abrupt neurological deterioration and rapidly progressive diffuse atrophy in a few months. A comprehensive diagnostic work-up and follow-up magnetic resonance imaging (MRI), including high-resolution advanced vessel-wall sequences, revealed underlying cerebral vasculitis. The novelty factors that the present report brings are the rapid progressive atrophy demonstrated on follow-up MRI in a patient with SLE, and the depiction of an underlying vasculitis on specific vessel-wall MRI techniques. We also reviewed the literature and discussed the main current applications of vessel-wall MRI sequences. The aim of the report is to recognize this dramatic form of presentation of NPSLE and the utility of the new MRI techniques for the diagnosis.


Effects of carbonated and noncarbonated beverages at specific intervals during treadmill running in the heat.
Eight male runners performed four 2-hr treadmill runs at 65% VO2max in the heat (35 degrees C, 15-20% RH). A different beverage was offered each trial and subjects drank ad libitum for 2 min every 20 min. The beverages were, 6% carbohydrate (CHO) solution (NC 6), 6% carbonated-CHO solution (C 6), 10% CHO solution (NC 10), and 10% carbonated-CHO solution (C 10). NC 6 and C 6 contained 4% sucrose and 2% glucose. NC 10 and C 10 contained high fructose corn syrup. Subjects drank more NC 6 than C 6. Fluid consumption was not different among other trials. During all trials, volume consumed and % delta PV declined while heart rate and rectal temperature increased (p < 0.05). No significant differences occurred between beverages for these variables. Percent body weight lost was greater (p < 0.05) for the C 10 trial compared to the NC 6 trial. Neither sweat rate, percent fluid replaced, plasma [Na+], [K+], osmolality, percent of drink volume emptied from the stomach, or glucose concentration differed among trials. Plasma [K+] and osmolality increased (p < 0.05) over time. Ratings of fullness and thirst were not different among beverages, although both perceptions increased (p < 0.05) with time. It is concluded that (a) carbonation decreased the consumption of the 6% CHO beverage; (b) fluid homeostasis and thermo-regulation were unaffected by the solutions ingested; and (c) fluid consumption decreased with time, while ratings of fullness and thirst increased.


Brain shift, level of consciousness, and restoration of consciousness in patients with acute intracranial hematoma.
Recently, Ropper reported that horizontal brain shift caused by acute unilateral mass lesions correlated closely with consciousness, and suggested that recovery of consciousness was unlikely to occur after surgical evacuation if the shift was insufficient to explain the observed diminution of consciousness. The authors have sought to confirm the correlation of pineal shift with level of consciousness and to assess the prognostic value of brain shift measurements in a prospective study. Forty-six patients (19 with subdural hematoma, 14 with intracerebral hematoma, and 13 with epidural hematoma) were accrued to the study group consecutively. A correlation was found between a decrease in the level of consciousness and a significant increase in the mean lateral brain displacement at the pineal gland (from 3.8 to 7.0 mm) and septum (5.4 to 12.2 mm). When outcome was examined in patients who were stuporous or comatose on admission, a significant increase in septal shift was found among patients with a poor outcome, but there was no significant relationship between outcome and degree of pineal or aqueductal shift. A poor outcome was more likely with effacement of both perimesencephalic cisterns or the ipsilateral cistern, but not the contralateral cistern, although this difference did not reach statistical significance. These results do not substantiate the value of brain shift as an independent prognostic factor after evacuation of an acute unilateral mass lesion. The decision to operate and the determination of prognosis should be based rather on established criteria such as the clinical examination, age of the patient, and the mechanism of injury.


Selective neurectomy of the gastrocnemius and soleus muscles for calf hypertrophy: an anatomical study and 700 clinical cases.
Calf hypertrophy is of concern to Asians. Liposuction and muscle resection are used with reasonable results. A technique of selective neurectomy of the medial gastrocnemius and soleus muscles is used to improve results of calf reduction. Between 1999 and 2006, 700 patients underwent neurectomy of the medial gastrocnemius and half of the soleus muscle without liposuction. Gait analysis was performed on six and electromyographic studies were performed on 20 patients. Preoperative circumference was 34.1 cm. An anatomical study was performed on seven cadaver limbs. All branches of the popliteal nerve were noted. Reduction in circumference was 2.67 cm at 14 months. Short-term disability was noted in 2.57 percent. Complications were noted in less than 5 percent. Dissatisfaction was noted in 4 percent (28 of 700 patients). Electromyography showed denervation of the medial gastrocnemius. Gait analysis revealed normal gait. Anatomical studies showed the nerve to the soleus had a medial and lateral branch (seven of seven). One twig of the medial branch of the soleus muscle pierced and innervated the medial gastrocnemius muscle (three of seven). Selective neurectomy can offer an effective method of reducing calf circumference and improving contour.


Characterization of a two-gene locus from Bartonella bacilliformis associated with the ability to invade human erythrocytes.
Bartonella bacilliformis, the agent of human Oroya fever, invades erythrocytes and causes a severe hemolytic anemia. The ability of two minimally invasive strains of Escherichia coli (DH5 alpha and HB101) to invade human erythrocytes was enhanced 6- to 39-fold by transformation with pIAL1, a plasmid containing a 1,469-bp BamHI fragment from the B. bacilliformis chromosome. Invasiveness was confirmed by gentamicin protection and transmission electron microscopy. DNA hybridization analysis confirmed the presence of the locus in B. bacilliformis KC583 and KC584 and its absence in E. coli chromosomal DNA. Sequencing of the DNA insert of pIAL1 revealed tandem open reading frames of 510 and 558 bp, designated ialA and ialB, respectively. Invasion assays with E. coli containing only an ialA or ialB recombinant suggest that both genes are necessary for invasiveness. The ialA gene is predicted to code for a polypeptide of 170 amino acids (20.1 kDa), and ialB is predicted to code for a polypeptide of 186 amino acids (19.9 kDa). In vitro transcription and translation of pIAL1 produced insert-specific protein bands with masses of approximately 21 and 20 kDa when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Expression of ialA and ialB in E. coli maxicells produced proteins with masses of approximately 21 kDa (IalA) and 18 kDa (IalB). Maxicell and computer analyses suggest that IalB contains an N-terminal secretory signal sequence which is posttranslationally cleaved. Searches of various DNA and protein databases revealed that IalA contains an N-terminal region of 35 amino acids with a high degree of homology to an NTPase consensus domain. There is 63.6% sequence conservation between the IalB protein and the invasion-associated protein Ail of Yersinia enterocolitica.


Trial of pyrethroid impregnated bednets in an area of Tanzania holoendemic for malaria. Part 2. Effects on the malaria vector population.
The malaria vector population consisted mainly of Anopheles gambiae s.s. with a small contribution from An. funestus and An. rivulorum. The mosquitoes coming to bite in bedrooms were monitored with light traps set beside untreated bednets. When impregnated bednets were provided for all the other beds in a village the Anopheles populations declined but the Culex quinquefasciatus populations were unaffected. The survival of An. gambiae (as measured by the mean number of ovarian dilatations) and the sporozoite rate declined following introduction of the nets and the estimated sporozoite inoculation rates into people not under their nets declined by more than 90%. The net introductions caused sharp declines in the number of mosquitoes resting indoors, but the evidence was inconclusive regarding diversion to outdoor resting, animal biting, earlier biting or outdoor biting. DDT spraying greatly reduced the Anopheles populations.


Uncovering a context-specific connectional fingerprint of human dorsal premotor cortex.
Primate electrophysiological and lesion studies indicate a prominent role of the left dorsal premotor cortex (PMd) in action selection based on learned sensorimotor associations. Here we applied transcranial magnetic stimulation (TMS) to human left PMd at low or high intensity while right-handed individuals performed externally paced sequential key presses with their left hand. Movements were cued by abstract visual stimuli, and subjects either freely selected a key press or responded according to a prelearned visuomotor mapping rule. Continuous arterial spin labeling was interleaved with TMS to directly assess how stimulation of left PMd modulates task-related brain activity depending on the mode of movement selection. Relative to passive viewing, both tasks activated a frontoparietal motor network. Compared with low-intensity TMS, high-intensity TMS of left PMd was associated with an increase in activity in medial and right premotor areas without affecting task performance. Critically, this increase in task-related activity was only present when movement selection relied on arbitrary visuomotor associations but not during freely selected movements. Psychophysiological interaction analysis revealed a context-specific increase in functional coupling between the stimulated left PMd and remote right-hemispheric and mesial motor regions that was only present during arbitrary visuomotor mapping. Our TMS perturbation approach yielded causal evidence that the left PMd is implicated in mapping external cues onto the appropriate movement in humans. Furthermore, the data suggest that the left PMd may transiently form a functional network together with right-hemispheric and mesial motor regions to sustain visuomotor mapping performed with the left nondominant hand.


Pain and mild traumatic brain injury: the implications of pain severity on emotional and cognitive functioning.
The aim of this study was to examine the effect of high chronic pain on (a) neuropsychological test performance and (b) self-reported emotional complaints in persons suffering from Postconcussional Disorders (PCD) after a mild traumatic brain injury (TBI). A two-group comparative research design was employed. An outpatient sample of 66 patients with mild TBI and PCD using the Ruff Neurobehavioural Inventory (RNBI) and a neuropsychological test battery. According to ANOVAs, no significant between-group differences were found on neuropsychological test performances; however, the high pain group had significantly more emotional residuals; particularly elevated on the RNBI were the Anger and Aggression, Anxiety, Depression and Paranoia and Suspicion sub-scales. Furthermore, an ANOVA found participants of the high pain group reporting significantly higher impairments on the RNBI Cognitive, Physical and Quality-of-Life composite scores and several RNBI sub-scales compared to their pre-morbid functioning. High chronic pain exacerbates the emotional aspect of PCD and, therefore, should be given special observance in treatment settings.


Loss of transforming growth factor beta type II receptor increases aggressive tumor behavior and reduces survival in lung adenocarcinoma and squamous cell carcinoma.
Lung adenocarcinoma and lung squamous cell carcinoma (SCC) are the most common non-small cell lung cancer (NSCLC) subtypes. This study was designed to determine whether reduced expression of TGFβ type II receptor (TGFβRII) promotes lung adenocarcinoma and SCC carcinogenesis. We examined TGFβRII expression at the protein and mRNA levels in human NSCLC samples and assessed the relationship between TGFβRII expression and clinicopathologic parameters. To determine whether sporadic TGFβRII deletion in airway epithelial cells induces NSCLC formation, we targeted TGFβRII deletion alone and in combination with oncogenic Kras(G12D) to murine airways using a keratin 5 (K5) promoter and inducible Cre recombinase. Reduced TGFβRII expression in human NSCLC is associated with male gender, smoking, SCC histology, reduced differentiation, increased tumor stage, increased nodal metastasis, and reduced survival. Homozygous or heterozygous TGFβRII deletion in mouse airway epithelia increases the size and number of Kras(G12D)-initiated adenocarcinoma and SCC. TGFβRII deletion increases proliferation, local inflammation, and TGFβ ligand elaboration; TGFβRII knockdown in airway epithelial cells increases migration and invasion. Reduced TGFβRII expression in human NSCLC is associated with more aggressive tumor behavior and inflammation that is, at least partially, mediated by increased TGFβ1 expression. TGFβRII deletion in mouse airway epithelial cells promotes adenocarcinoma and SCC formation, indicating that TGFβRII loss plays a causal role in lung carcinogenesis. That TGFβRII shows haploid insufficiency suggests that a 50% TGFβRII protein reduction would negatively impact lung cancer prognosis.


B cell antigen receptor-mediated apoptosis. Importance of accessory molecules CD19 and CD22, and of surface IgM cross-linking.
Engagement of the B cell Ag receptor can induce a suicide pathway in various B cell types. Earlier studies showed that anti-IgM mAb treatment triggers apoptotic death in the Burkitt lymphoma-derived cell line, Ramos. We show that two B cell surface molecules, CD19 and CD22, which have been reported to interact either functionally or structurally with the B cell Ag receptor, also stimulate cell suicide when sufficiently aggregated, both in the Ramos and EBV-infected Ramos AW cell lines. In conditions of lower cross-linking, both molecules enhance the apoptotic response induced by a suboptimal dose of anti-IgM mAb in Ramos cells, reinforcing the notion that CD19 and CD22 may be involved in the death pathway and modulate Ag-induced B cell apoptosis. Similar outcomes were obtained with human tonsillar B cells, which enter the death program upon treatment with cross-linked anti-IgM, -CD19, or -CD22 mAbs. These results indicate that Ag-induced B cell suicide may affect mature B cells in the periphery and may be regulated via the interaction of CD19 and/or CD22 with their respective ligand(s). Early tyrosine phosphorylations were analyzed by Western blotting. The biologic outcome of these various treatments--cell survival or death--could not be related to any detectable new tyrosine-phosphorylated substrate, further questioning the biochemical basis of apoptosis signaling.


Helical tomotherapy-based STAT stereotactic body radiation therapy: Dosimetric evaluation for a real-time SBRT treatment planning and delivery program.
Stereotactic body radiation therapy (SBRT) treatments have high-dose gradients and even slight patient misalignment from the simulation to treatment could lead to target underdosing or organ at risk (OAR) overdosing. Daily real-time SBRT treatment planning could minimize the risk of geographic miss. As an initial step toward determining the clinical feasibility of developing real-time SBRT treatment planning, we determined the calculation time of helical TomoTherapy-based STAT radiation therapy (RT) treatment plans for simple liver, lung, and spine SBRT treatments to assess whether the planning process was fast enough for practical clinical implementation. Representative SBRT planning target volumes for hypothetical liver, peripheral lung, and thoracic spine lesions and adjacent OARs were contoured onto a planning computed tomography scan (CT) of an anthropomorphic phantom. Treatment plans were generated using both STAT RT "full scatter" and conventional helical TomoTherapy "beamlet" algorithms. Optimized plans were compared with respect to conformality index (CI), heterogeneity index (HI), and maximum dose to regional OARs to determine clinical equivalence and the number of required STAT RT optimization iterations and calculation times were determined. The liver and lung dosimetry for the STAT RT and standard planning algorithms were clinically and statistically equivalent. For the liver lesions, "full scatter" and "beamlet" algorithms showed a CI of 1.04 and 1.04 and HI of 1.03 and 1.03, respectively. For the lung lesions, "full scatter" and "beamlet" algorithms showed a CI of 1.05 and 1.03 and HI of 1.05and 1.05, respectively. For spine lesions, "full scatter" and "beamlet" algorithms showed a CI of 1.15 and 1.14 and HI of 1.22 and 1.14, respectively. There was no difference between treatment algorithms with respect to maximum doses to the OARs. The STAT RT iteration time with current treatment planning systems is 45 sec, and the treatment planning required 3 iterations or 135 sec for STAT RT liver and lung SBRT plans and 7 iterations or 315 sec for STAT RT spine SBRT plans. Helical TomoTherapy-based STAT RT treatment planning with the "full scatter" algorithm provides levels of dosimetric conformality, heterogeneity, and OAR avoidance for SBRT treatments that are clinically equivalent to those generated with the Helical TomoTherapy "beamlet" algorithm. STAT RT calculation times for simple SBRT treatments are fast enough to warrant further investigation into their potential incorporation into an SBRT program with daily real-time planning. Development of methods for accurate target and OAR determination on megavoltage computed tomography scans incorporating high-resolution diagnostic image co-registration software and CT detector-based exit dose measurement for quality assurance are necessary to build a real-time SBRT planning and delivery program.


Combinatorial control required for the specificity of yeast MAPK signaling.
In yeast, an overlapping set of mitogen-activated protein kinase (MAPK) signaling components controls mating, haploid invasion, and pseudohyphal development. Paradoxically, a single downstream transcription factor, Ste12, is necessary for the execution of these distinct programs. Developmental specificity was found to require a transcription factor of the TEA/ATTS family, Tec1, which cooperates with Ste12 during filamentous and invasive growth. Purified derivatives of Ste12 and Tec1 bind cooperatively to enhancer elements called filamentation and invasion response elements (FREs), which program transcription that is specifically responsive to the MAPK signaling components required for filamentous growth. An FRE in the TEC1 promoter functions in a positive feedback loop required for pseudohyphal development.


High Expression of miR-532-5p, a Tumor Suppressor, Leads to Better Prognosis in Ovarian Cancer Both In Vivo and In Vitro.
Ovarian cancer is the leading cause of death for gynecologic cancers, ranking fifth overall for cancer-related death among women. The identification of biomarkers and the elucidation of molecular mechanisms for improving treatment options have received extensive efforts in ovarian cancer research. miRNAs have high potential to act as both ovarian cancer biomarkers and as critical regulators of ovarian tumor behavior. We comprehensively analyzed global mRNA, miRNA expression, and survival data for ovarian cancer from The Cancer Genome Atlas (TCGA) to pinpoint miRNAs that play critical roles in ovarian cancer survival through their effect on mRNA expression. We performed miRNA overexpression and gene knockdown experiments to confirm mechanisms predicted in our bioinformatics approach. We established that overexpression of miR-532-5p in OVCAR-3 cells resulted in a significant decrease in cell viability over a 96-hour time period. In the TCGA ovarian cancer dataset, we found 67 genes whose expression levels were negatively correlated with miR-532-5p expression and correlated with patient survival, such as WNT9A, CSNK2A2, CHD4, and SH3PXD2A The potential miR-532-5p-regulated gene targets were found to be enriched in the Wnt pathway. Overexpression of miR-532-5p through miRNA mimic caused downregulation of CSNK2A2, CHD4, and SH3PXD2A in the OVCAR-3 cell line. We have discovered and validated the tumor-suppressing capabilities of miR-532-5p both in vivo through TCGA analysis and in vitro through ovarian cancer cell lines. Our work highlights the potential clinical importance of miR-532-5p expression in ovarian cancer patients. Mol Cancer Ther; 15(5); 1123-31. ©2016 AACR.


Development and Validation of a Novel Robotic Procedure Specific Simulation Platform: Partial Nephrectomy.
We developed a novel procedure specific simulation platform for robotic partial nephrectomy. In this study we prospectively evaluate its face, content, construct and concurrent validity. This hybrid platform features augmented reality and virtual reality. Augmented reality involves 3-dimensional robotic partial nephrectomy surgical videos overlaid with virtual instruments to teach surgical anatomy, technical skills and operative steps. Advanced technical skills are assessed with an embedded full virtual reality renorrhaphy task. Participants were classified as novice (no surgical training, 15), intermediate (less than 100 robotic cases, 13) or expert (100 or more robotic cases, 14) and prospectively assessed. Cohort performance was compared with the Kruskal-Wallis test (construct validity). Post-study questionnaire was used to assess the realism of simulation (face validity) and usefulness for training (content validity). Concurrent validity evaluated correlation between virtual reality renorrhaphy task and a live porcine robotic partial nephrectomy performance (Spearman's analysis). Experts rated the augmented reality content as realistic (median 8/10) and helpful for resident/fellow training (8.0-8.2/10). Experts rated the platform highly for teaching anatomy (9/10) and operative steps (8.5/10) but moderately for technical skills (7.5/10). Experts and intermediates outperformed novices (construct validity) in efficiency (p=0.0002) and accuracy (p=0.002). For virtual reality renorrhaphy, experts outperformed intermediates on GEARS metrics (p=0.002). Virtual reality renorrhaphy and in vivo porcine robotic partial nephrectomy performance correlated significantly (r=0.8, p <0.0001) (concurrent validity). This augmented reality simulation platform displayed face, content and construct validity. Performance in the procedure specific virtual reality task correlated highly with a porcine model (concurrent validity). Future efforts will integrate procedure specific virtual reality tasks and their global assessment.


Predictors of diabetes in older people in urban China.
China has the largest number of people with diabetes in the world. Over the last 30 years China has experienced rapid economic growth and a growing income gap between rich and poor. The population is ageing, however diabetes in older people has not been well studied to date. In this study we determined incidence and predictors of diabetes in older Chinese people. During 2001, using a standard interview method, we examined 1,317 adults aged ≥65 years who did not have diabetes in the city of Hefei, and characterized baseline risk factors. Over 7.5 years of follow up, we documented incident diabetes using self-reported doctor diagnosis and the cause of death in the whole cohort, and HbA(1C) ≥48 mmol/mol in a nested case-control sample. A multivariate Cox regression model was employed to investigate risk of diabetes in relation to baseline risk factors. During follow up, 119 persons had newly diagnosed diabetes. World age-standardised incidence of diabetes was 24.5 (95% CI 19.5-29.5) per 1,000 person-years. Risk of diabetes was significantly and positively associated with income, waist circumference and body mass index, smoking and uncontrolled hypertension, but negatively associated with having a hobby of walking and frequency of visiting children/other relatives and contacting neighbours/friends. Higher income was significantly associated with increased diabetes risk regardless of cardiovascular and psychosocial risk factors. Compared to those with middle income and no psychosocial risk factors, the hazard ratio for incident diabetes among participants with high income and psychosocial risk was 2.13 (95% CI 1.02-4.45). Increasing incidence of diabetes in relation to high income has become an important public health issue in China. Maintaining social networks and gentle physical activities and reducing psychosocial factors may be integrated into current multi-faceted preventive strategies for curbing the epidemic of diabetes in the older population.


Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography.
Liver stiffness, noninvasively measured by transient elastography, correlates well with liver fibrosis stage. The aim of this prospective study was to evaluate the liver stiffness measurement (LSM) as a predictor of hepatocellular carcinoma (HCC) development among patients with chronic hepatitis C. Between December 2004 and June 2005, a total of 984 HCV-RNA positive patients, without HCC or a past history of it, visited the University of Tokyo Hospital. LSM was performed successfully in 866 patients, who gave informed consent. During the follow-up period (mean, 3.0 years), HCC developed in 77 patients (2.9% per 1 person-year). The cumulative incidence rates of HCC at 1, 2, and 3 years were 2.4%, 6.0%, and 8.9%, respectively. Adjusting for other significant factors for HCC development, patients with higher LSM were revealed to be at a significantly higher risk, with a hazard ratio, as compared to LSM < or =10 kPa, of 16.7 (95% confidence interval [CI], 3.71-75.2; P < 0.001) when LSM 10.1-15 kPa, 20.9 (95% CI, 4.43-98.8; P < 0.001) when LSM 15.1-20 kPa, 25.6 (95%CI, 5.21-126.1; P < 0.001) when LSM 20.1-25 kPa, and 45.5 (95% CI, 9.75-212.3; P < 0.001) when LSM >25 kPa. This prospective study has shown the association between LSM and the risk of HCC development in patients with hepatitis C. The utility of LSM is not limited to a surrogate for liver biopsy but can be applied as an indicator of the wide range of the risk of HCC development.


MafA is required for postnatal proliferation of pancreatic β-cells.
The postnatal proliferation and maturation of insulin-secreting pancreatic β-cells are critical for glucose metabolism and disease development in adults. Elucidation of the molecular mechanisms underlying these events will be beneficial to direct the differentiation of stem cells into functional β-cells. Maturation of β-cells is accompanied by increased expression of MafA, an insulin gene transcription factor. Transcriptome analysis of MafA knockout islets revealed MafA is required for the expression of several molecules critical for β-cell function, including Glut2, ZnT8, Granuphilin, Vdr, Pcsk1 and Urocortin 3, as well as Prolactin receptor (Prlr) and its downstream target Cyclin D2 (Ccnd2). Inhibition of MafA expression in mouse islets or β-cell lines resulted in reduced expression of Prlr and Ccnd2, and MafA transactivated the Prlr promoter. Stimulation of β-cells by prolactin resulted in the phosphorylation and translocation of Stat5B and an increased nuclear pool of Ccnd2 via Prlr and Jak2. Consistent with these results, the loss of MafA resulted in impaired proliferation of β-cells at 4 weeks of age. These results suggest that MafA regulates the postnatal proliferation of β-cells via prolactin signaling.


India and management of COVID-19: A case study on published guidelines.
In the face of the ongoing pandemic, the primary care physicians in India are dealing not only with an increased number of patients but are also facing difficulties in the management of complex critically ill patients. To guide the management plans of primary care physicians, several guidelines have been published by the central and state health bodies. In such a situation, an updated and unifying state, national and international guidelines based on critical analysis and appraisal of evolving data is the need of the hour. In this review, we critically analysed the current existing guidelines that have been formulated within India in light of recent evidence.


Natural history of headache after traumatic brain injury.
Headache is one of the most common persisting symptoms after traumatic brain injury (TBI). Yet there is a paucity of prospective longitudinal studies of the incidence and prevalence of headache in a sample with a range of injury severity. We sought to describe the natural history of headache in the first year after TBI, and to determine the roles of prior history of headache, sex, and severity of TBI as risk factors for post-traumatic headache. A cohort of 452 acute, consecutive patients admitted to inpatient rehabilitation services with TBI were enrolled during their inpatient rehabilitation from February 2008 to June 2009. Subjects were enrolled across 7 acute rehabilitation centers designated as TBI Model Systems centers. They were prospectively assessed by structured interviews prior to inpatient rehabilitation discharge, and at 3, 6, and 12 months after injury. Results of this natural history study suggest that 71% of participants reported headache during the first year after injury. The prevalence of headache remained high over the first year, with more than 41% of participants reporting headache at 3, 6, and 12 months post-injury. Persons with a pre-injury history of headache (p<0.001) and females (p<0.01) were significantly more likely to report headache. The incidence of headache had no relation to TBI severity (p=0.67). Overall, headache is common in the first year after TBI, independent of the severity of injury range examined in this study. Use of the International Classification of Headache Disorders criteria requiring onset of headache within 1 week of injury underestimates rates of post-traumatic headache. Better understanding of the natural history of headache including timing, type, and risk factors should aid in the design of treatment studies to prevent or reduce the chronicity of headache and its disruptive effects on quality of life.


Flexible TWDM PON system with pluggable optical transceiver modules.
A flexible TWDM PON system is proposed which allows pay-as-you-grow in capacity, supports load balancing among different ODNs, and achieves significant power saving at OLT. Integrated OLT transceiver in enhanced CFP module and low-cost tunable ONU transceiver in SFP+ module are developed, for the first time, for cost effective deployment of TWDM PONs. System experiments demonstrate error free performance with 36 dB power budget in a flexible TWDM PON test bed.


Improving of red colorants production by a new Penicillium purpurogenum strain in submerged culture and the effect of different parameters in their stability.
There is a worldwide interest in the development of processes for colorants production from natural sources such as microorganism. The aim of this study was to optimize red colorants production by Penicillium purpurogenum DPUA 1275 and to evaluate the effect of pH, temperature, salts and polymers on the stability of these colorants. Under optimized conditions, a 78% increase in red colorants production was achieved. The best pH and temperature conditions were obtained at pH 8.0 and 70°C, respectively. In the presence of salts NaCl and Na2 SO4 , both at concentrations of 0.1 and 0.5 M in Mcllvaine buffer (pH 8.0), the red colorants showed good stability. In the presence of both polymers polyethylene glycol and sodium polyacrylate, the red colorants kept their color intensity. Thus, this study presents characteristics of red colorants produced by P. purpurogenum that can be applied in different industries after toxicological examination.


Hotspot autoimmune T cell receptor binding underlies pathogen and insulin peptide cross-reactivity.
The cross-reactivity of T cells with pathogen- and self-derived peptides has been implicated as a pathway involved in the development of autoimmunity. However, the mechanisms that allow the clonal T cell antigen receptor (TCR) to functionally engage multiple peptide-major histocompatibility complexes (pMHC) are unclear. Here, we studied multiligand discrimination by a human, preproinsulin reactive, MHC class-I-restricted CD8+ T cell clone (1E6) that can recognize over 1 million different peptides. We generated high-resolution structures of the 1E6 TCR bound to 7 altered peptide ligands, including a pathogen-derived peptide that was an order of magnitude more potent than the natural self-peptide. Evaluation of these structures demonstrated that binding was stabilized through a conserved lock-and-key-like minimal binding footprint that enables 1E6 TCR to tolerate vast numbers of substitutions outside of this so-called hotspot. Highly potent antigens of the 1E6 TCR engaged with a strong antipathogen-like binding affinity; this engagement was governed though an energetic switch from an enthalpically to entropically driven interaction compared with the natural autoimmune ligand. Together, these data highlight how T cell cross-reactivity with pathogen-derived antigens might break self-tolerance to induce autoimmune disease.


Anti-tumour effects of triple therapy with octreotide, galanin and serotonin in comparison with those of 5-fluorouracil/leukovorin on human colon cancer.
Human colon cancer cells were injected subcutaneous in nude mice. After 8 days the animals were divided in two groups, the first group received triple therapy with octreotide, galanin and serotonin (40 microg/kg body weight/day) through an ALZET osmotic pump implanted intraperitoneally (i.p.) for 14 days, followed by 5 days of subcutaneous injections (200 microg/kg body weight/ day). The second group was injected i.p. for 5 days with 5-fluorouracil/leukovorin (5-FU/LV) at concentrations of 4 mg and 2 mg/kg body weight, respectively. After 9 days without any treatment, the mice received i.p. injection with 5-FU/LV (20 mg and 10 mg/kg body weight/day, respectively) for another 5 days. The volume and weight of the tumours were measured at the end of the experiment. Apoptosis, proliferation, blood vessels, epidermal growth factor (EGF) and vascular endothelial cell growth factor (VEGF) were detected with immunocytochemistry. Apoptosis was also detected using the TUNEL-method. Quantification was performed using computed image analysis. There was no statistical significance between tumours treated with 5-FU/LV or triple therapy regarding the volume and weights of the tumours, apoptotic, proliferation, VEGF indces and the density of tumour blood vessels. The EGF labelling index was, however significantly lower in the tumours treated with triple therapy than those treated with 5-FU/LV. In conclusion, treatment with triple therapy using octreotide, galanin and serotonin appear to be comparable with 5-FU/LV that is the standard chemotherapeutic agent for colorectal cancer.


Effectiveness of intensive cognitive behavioral therapy in adolescents and adults with anorexia nervosa.
This study aimed to compare the effectiveness of an intensive treatment based on enhanced cognitive behavioral therapy (CBT-E) in adolescent and adult patients with anorexia nervosa. A total of 150 consecutive patients (74 adolescents and 81 adults) were admitted to a 20-week intensive CBT-E program (13 weeks of inpatient followed by 7 weeks of day-hospital treatment). All patients had responded poorly to previous outpatient treatments and were assessed at admission, end of treatment (EOT), and 20- and 60-week follow-ups. About 70% of eligible patients began the program, and more than 85% completed it. Body mass index (BMI) in adults and BMI-for-age percentile in adolescents improved significantly from baseline to EOT, remained stable until 20-week follow-up, and slightly decreased from 20-week follow-up to 60-week follow-up, while remaining in the lower normal range. Eating disorder psychopathology, general psychopathology, and clinical impairment scores decreased significantly at EOT and showed only a slight increase from EOT to follow-ups. No difference was found between adolescent and adult patients in treatment acceptance, dropout, or any outcome measure. These findings indicate that intensive CBT-E seems to be an effective treatment for severely ill adolescent and adult patients with anorexia nervosa.


Verbal Semantics Drives Early Anticipatory Eye Movements during the Comprehension of Verb-Initial Sentences.
Studies on anticipatory processes during sentence comprehension often focus on the prediction of postverbal direct objects. In subject-initial languages (the target of most studies so far), however, the position in the sentence, the syntactic function, and the semantic role of arguments are often conflated. For example, in the sentence "The frog will eat the fly" the syntactic object ("fly") is at the same time also the last word and the patient argument of the verb. It is therefore not apparent which kind of information listeners orient to for predictive processing during sentence comprehension. A visual world eye tracking study on the verb-initial language Tagalog (Austronesian) tested what kind of information listeners use to anticipate upcoming postverbal linguistic input. The grammatical structure of Tagalog allows to test whether listeners' anticipatory gaze behavior is guided by predictions of the linear order of words, by syntactic functions (e.g., subject/object), or by semantic roles (agent/patient). Participants heard sentences of the type "Eat frog fly" or "Eat fly frog" (both meaning "The frog will eat the fly") while looking at displays containing an agent referent ("frog"), a patient referent ("fly") and a distractor. The verb carried morphological marking that allowed the order and syntactic function of agent and patient to be inferred. After having heard the verb, listeners fixated on the agent irrespective of its syntactic function or position in the sentence. While hearing the first-mentioned argument, listeners fixated on the corresponding referent in the display accordingly and then initiated saccades to the last-mentioned referent before it was encountered. The results indicate that listeners used verbal semantics to identify referents and their semantic roles early; information about word order or syntactic functions did not influence anticipatory gaze behavior directly after the verb was heard. In this verb-initial language, event semantics takes early precedence during the comprehension of sentences, while arguments are anticipated temporally more local to when they are encountered. The current experiment thus helps to better understand anticipation during language processing by employing linguistic structures not available in previously studied subject-initial languages.


Joint modeling of RNase footprint sequencing profiles for genome-wide inference of RNA structure.
Recent studies have revealed significant roles of RNA structure in almost every step of RNA processing, including transcription, splicing, transport and translation. RNase footprint sequencing (RNase-seq) has emerged to dissect RNA structures at the genome scale. However, it remains challenging to analyze RNase-seq data because of the issues of signal sparsity, variability and correlations among various RNases. We present a probabilistic framework, joint Poisson-gamma mixture (JPGM), for integrative modeling of multiple RNase-seq profiles. Combining JPGM with hidden Markov model allows genome-wide inference of RNA structures. We apply the joint modeling approach for inferring base pairing states on simulated data sets and RNase-seq profiles of the double-strand specific RNase V1 and single-strand specific RNase S1 in yeast. We demonstrate that joint analysis of V1 and S1 profiles outputs interpretable RNA structure states, while approaches that analyze each profile separately do not. The joint modeling approach predicts the structure states of all nucleotides in 3196 transcripts of yeast without compromising accuracy, while the simple thresholding approach misses 43% of the nucleotides. Furthermore, the posterior probabilities outputted by our model are able to resolve the structural ambiguity of ≈300 000 nucleotides with overlapping V1 and S1 cleavage sites. Our model also generates RNA accessibilities, which are associated with three-dimensional conformations.


Multi-μJ, CEP-stabilized, two-cycle pulses from an OPCPA system with up to 500 kHz repetition rate.
We present a two-stage OPCPA system based on a Ti:sapphire seed and a thin-disk regenerative amplifier producing compressed pulse energies of more than 3 μJ and durations of less than 6 fs at a high repetition rate of 143 kHz. In combination with the obtained CEP stability and the repetition rate scalability between 100 and 500 kHz the system forms an ideal tool for high field and phase sensitive spectroscopic experiments.


I-proteins - a proposed switch in myotubularin function.
In this article, we consider the functions of the myotubularins - a large family of phosphoinositide 3-phosphatases. By analogy with the phosphatidylinositol 3-phosphatase PTEN (phosphatase and tensin homolog deleted in chromosome ten) and many protein phosphatases, it has been proposed that the primary function of this protein family is to regulate substrate levels, in this case phosphatidylinositol (3)-phosphate. We propose an alternate, or additional, function that is analogous to the G-protein family of phosphatases, which use nucleotide-dependent conformational changes to transduce signals or do mechanical work.